Over the malaria transmission season from June 2011 until December 2011, we enrolled 967 acute episodes of P. falciparum malaria, from which samples were obtained. The day 21 follow up visits were completed end of January 2012. All samples were shipped to the USA in February / March 2012. We have archived the samples here in Rockville. In the interim, we have established the flow-cytometric assays and the RT PCR experiments we aim to perform on these samples. In May 2012, we began performing the above described experiments. In FY 13, we have completed the laboratory assays on those samples, and are at an advanced stage of data analysis. Further background information: In a longitudinal experimental human P. falciparum infection model where malaria nave volunteers undergo sporozoite challenge, we previously described that malaria induces functionally competent regulatory T cells (Treg) which was associated with reduced pro-inflammatory responses and faster parasite growth. Subsequently, we established that natural exposure to malaria is associated with a transient increase of Treg, that express an effector-memory phenotype and are prone to apoptosis . Detailed description of study procedures: In a hospital based study investigating children with SM and UM we found that the amount of Treg induced during an acute infection is inversely correlated to the magnitude of malaria specific T cell memory responses, an observation we also confirmed in sporozoite challenged volunteers. Thus, we hypothesize that malaria-specific Treg acquired or activated during a primary infection may limit the magnitude of malaria specific Th1 memory responses to subsequent infections to a level that still allows parasite clearance but with a substantially reduced risk of immunopathology, which may be part of the long sought-after mechanism that protects against SM after minimal exposure only. During the malaria transmission season 2011, every child up to 10 years of age presenting with clinical malaria and a valid parental consent, was asked to donate 1ml of blood that was collected into an RNA preservative. An aliquot of this RNA will be used to measure FOXP3 mRNA and 2 house-keeping genes. Another 4mls (children below 2 years of age) or 8mls (children above 2 years) of blood was collected into a heparinized tube from which plasma and PBMC were prepared and cryopreserved. On day 21 (+/- 3 days), a 5 mls blood sample was collected into a heparinized tube from which plasma and PBMC were prepared and cryopreserved. Samples were shipped to the USA and were subject to laboratory investigations. We expect to complete the data analysis by end of calendar year 2013.